Advances in the treatment of cardiovascular diseases and obstructive vascular diseases have led to treatments for a range of illnesses and conditions. These treatments, which include implantation of numerous varieties of drug-eluting and non-drug-eluting devices, have dramatically improved survival and the quality of life of patients. However, these treatments are not without limitations and side-effects.
Medical therapies focus on reducing the risk factors associated with obstructive vascular disease. Anti-thrombotic, anti-hypertensive, and cholesterol-lowering medications are aimed at decreasing the risk of occlusion, while beta-blockers and angiotensin-converting enzyme inhibitors act by reducing the workload of the heart. Despite these pharmaceutical advances that reduce the risk of vascular occlusion and cardiac events, the need for interventional cardiology and cardiac surgery to directly treat cardiovascular diseases and vascular obstructions remains immense.
Angioplasty is the major intervention for coronary artery disease accounting for over 680,000 procedures annually in the United States alone. Briefly, a balloon is placed within a blocked artery and expanded to relieve the obstruction. In most cases, a stent is placed within the instrumented artery. However, only 70% of angioplasties lead to long-term (6 months) relief of vascular obstruction. In a process termed restenosis, vascular smooth muscle cells reocclude the artery in response to the vascular injury caused by angioplasty. Such restenosis is also observed in other procedures which cause injury to a body vessel wall including the placement of stents, wires, catheters, shunts, or other intraluminal devices in any body vessel (e.g., in an artery, vein, ureter, urethra, Fallopian tube, common bile duct, pancreatic duct, kidney duct, esophagus, trachea, bladder, uterus, ovarian duct, vas deferens, prostatic duct, or lymphatic duct.). Continued advances in the geometry and composition of stents have largely impacted ease of stent delivery, but have not lessened the complication of restenosis. Recently, strategies employing radioactivity and other cytotoxic agents (e.g. paclitaxil, actinomycind, and rapamycin) to treat restenosis have received substantial attention. These strategies rely on the temporary and local delivery of toxic agents that block proliferation of many cell types. The long-term efficacy is currently being tested; however the toxicity of these agents raises serious doubts of whether they can be used as a long term treatment option for managing often chronic cardiac and cardiovascular conditions.
Current therapies for cardiovascular and obstructive vascular diseases aim to prevent or inhibit the hyperproliferation of the vascular smooth muscle cells lining vessels, thereby preventing or inhibiting occlusion of the vessel. However, many of the therapies, including rapamycin and taxol, used to inhibit proliferation of vascular smooth muscle cells function via a cytotoxic mechanism. Although these therapies may help prevent occlusion, their cytotoxicity inhibits endothelial cells within or adjacent to vessels. Damage to endothelial cell growth or structure is further exacerbated by insertion of intraluminal devices which are often used to deliver these and other therapeutic agents. A combination of the damage caused by the therapeutic agents and/or damage caused by the insertion of various devices often leads to restenosis. As a result of restenosis, patients with cardiovascular and occlusive vascular diseases must often be repeatedly stented, catheterized, or otherwise treated. Such repeated treatment exposes the patients to increased risks associated with any hospitalization or invasive procedure. Furthermore, the need to repeat these treatments dramatically increases the costs associated with managing these conditions. Methods and compositions that decrease or prevent restenosis would provide a substantial improvement in the art.
In addition to the problem of restenosis, thrombosis is a significant problem associated with many of the current treatments for cardiovascular diseases and occlusive vascular diseases. In fact, the risk of thrombosis exists whenever a device is placed and left in the body, and is thus a potential complication of many surgical procedures. Thus, thrombosis is a serious complication associated not only with cardiac and intravascular procedures, but also with other interventional approaches involving the placing of devices into the body or into the lumens of body vessels. Specifically, and as outlined above, many of the current drug therapies damage endothelial cells and then inhibit their proliferation. This significantly inhibits endothelialization of inserted devices. As a result, late thrombosis may occur in patients treated using a drug-eluting or non-drug-eluting device. To help prevent potentially lethal thrombosi, patients are often aggressively treated (sometimes on a long term basis) with anti-platlet and/or anti-coagulent therapies. These treatments impose their own risks and costs. Accordingly, methods and compositions that promote endothelization of inserted devices (e.g., intravascular or other intraluminal devices), thereby preventing or decreasing the likelihood of thrombosis would be a significant improvement in the art.
The present invention provides methods and compositions for promoting adhesion of endothelial cells, for example, for promoting adhesion of endothelial cells to implantable, biocompatible devices. Methods and compositions for promoting adhesion of endothelial cells, for example, to biocompatible devices, can be used in the treatment or prevention of restenosis and/or thrombosis.